Alcoholism is a major public health problem responsible for large scale morbidity and mortality and can be defined as a chronic psychiatric disorder in which a pattern of pathological alcohol use leads to serious personal and physical distress. Alcohol addiction or dependence implies a loss of control over the desire to consume ethanol. Between 80% and 90% of the population in the United States drink alcohol at some time during their lives and 30% to 40% of these may develop some temporary alcohol related problems.
Therapy in a hospital or other specialized controlled structure is the most common place for the treatment of alcohol addiction or abuse. Treatments that are used may be classified as either psychotherapy or psychopharmacology. Psychotherapies include counseling, participation in self help groups such as Alcoholics Anonymous, and the like. The generally recognized psychopharmacological treatment of ethanol withdrawal symptoms and physical changes is the administration of a mild tranquilizer such as chlordiazepoxide. Additionally, vitamins, in particular the B vitamins are administered. Optionally, magnesium sulfate and/or glucose are also administered.
While alcohol withdrawal rarely precipitates a major medical problem, alcoholic relapse after discharge of a patient from the controlled setting is very frequent. In addition to continuous psychotherapy, long term pharmacotherapies generally include an alcohol deterring agent in the treatment of alcoholics. Most of these agents have deleterious side effects that discourage continuous usage by the patient. One of the most frequently prescribed alcohol deterring agents is disulfiram. Disulfiram functions as an aldehyde dehydrogenase inhibitor. When taken with alcohol, disulfiram induces a highly unpleasant condition called the disulfiram-alcohol reaction (DAR). This highly unpleasant condition is due to the accumulation of acetaldehyde, an intermediate metabolite of alcohol. The symptoms of DAR include altered blood pressure, pulse rate, respiration rate, flushing, heat sensation, nausea, vomiting, palpitations, breathlessness and headaches. Although disulfiram is effective at making consumption of alcohol an uncomfortable experience, disulfiram does not reduce the desire for alcohol nor influence the underlying causes of the disease. This is true for many of the alcohol deterring agents prescribed. Moreover, in many cases, the symptoms from using disulfiram reach an unsafe level of circulatory changes that requires discontinuation of the treatment. As a result, patients do not feel ill enough to abstain from drinking.
While both psychotherapy and pharmacotherapy have proven to yield limited success, there still exists a need for pharmacotherapeutic agents that can attenuate the desire for alcohol with minimal or no deleterious side effects. Additionally, it is desirable for such an agent to be process selective in that it reduces alcohol dependence, but not food and water consumption. Opiates, such as morphine, naltrexone and naloxone, are believed to reduce alcohol desire by a generalized suppression of food intake and water. However, not all anorectics reduce alcohol desire. Appetite control is one of the most complex human behaviors which involves neurotransmitter systems at both the periphery and the central nervous system. This is further complicated by the chemical and pharmacological nature of the different anorectic agents that have been or are being used to control appetite. As a result, it is not possible to predict from appetite modulatory data the potential of an agent to decrease preference for alcohol.
Histidyl-proline diketopiperazine was discovered to be a major metabolite of TRH in 1976. The cyclic dipeptide, endogenous to mammals, is ubiquitously distributed throughout the central nervous system and has been shown to elicit a number of endocrine and central nervous system-related biological functions including: elevation of brain cyclic GMP concentrations; inhibition of ethanol induced sleep; decrease in food intake; hypothermia in rats; attenuation of ketamine-induced anesthesia; inhibition of dopamine uptake by rat brain striatal synaptosomes; and inhibition of prolactin secretions in vitro.
Surprisingly, applicant has discovered that histidyl-proline diketopiperazine can be useful for treating the cessation or withdrawal from the use of alcohol. In particular, histidyl-proline diketopiperazine has been found to reduce the desire for alcohol. The applicant has further discovered that the dosages required to attenuate the desire for alcohol are generally less than those dosages used for effecting appetite or water suppression.